Previous neuroendocrine studies in patients with depression have focused upon hormonal response patterns to provocative stimula. Such studies have tended to neglect the dynamic nature of the neuroendocrine axis. Plasma hormone concentration is the net result of hormone synthesis, secretion, binding and degradation. Each of these processes is both stimulus mediated and feedback modulated through specific cellular recognition sites or receptors. Such receptors occur at the end-organ target cell and are clearly critical components in neuroendocrine regulation. Thus hormone-receptor interactions are a major determinant of cellular responsivity and modulation of such interactions provides a sensitive way of regulating cellular activity. This project focuses upon the central role of receptors for hormones and neurotransmitters in neuroendocrine control and will define neuroendocrine disturbances in depressed patients by directly evaluating hormone-receptor interactions. Disturbances at this key regulatory point could result in marked disturbances in cellular activity which might well manifest as a behavioral or emotional disturbance. Disturbances in hormone-receptor interactions are being recognized in many clinical syndromes and in view of the overactivity in the hypothalamic-pituitary axis in some depressed patients it appears prudent to evaluate regulation of this axis at a cellular level. By using appropriately labelled opiocortin peptides and steroid hormones, receptor binding and responsivity can be measured. In man, leucocytes provide a useful tissue source for such studies. Receptor binding assays will be established for ACTH and Beta-endorphin and their circadian secretory profiles will be established in depressed patients. The roles of ACTH, Beta-endorphin and cortisol in the central nervous system are poorly understood although they have been implicated in the etiology of severe depression. Therefore the binding and effects of these hormones on neurons and hypothalamic cells will be directly measured using nerve cells in tissue culture.